tbuckley/cabot-search huggingface dataset:
The Wnt signaling pathway in gastrointestinal cancers.
Authors: Zoran Gatalica, Turgut W Dogruluk, Pawan Noel, Susan M. Dombrowski, Lenny Hong, Michelle Barbi, Thiruppavai Chandrasekaran, Gargi D. Basu, David W. Hall, Jess R Hoag, Madappa N. Kundranda
Journal: Journal of Clinical Oncology (2023)

807 Background: Activation of the Wnt signaling pathway leads to increases in β-catenin levels, which subsequently increases transcription of various genes, including those involved in cell proliferation. Dysregulation of the Wnt signaling pathway has been observed in numerous gastrointestinal (GI) cancers. Here we examine Wnt pathway activation across all GI cancers by investigating alterations in certain genes of the Wnt pathway, which may identify patients eligible for clinical trials. Methods: The Oncomap ExTra genomic profiling assay utilizes tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations in tumors. The assay detects single-nucleotide substitutions, indels, copy number alterations, alternative transcripts, and gene fusions. Alterations in genes that activate Wnt signaling and their frequency across all GI cancers was determined. Results: A total of 1928 patients assayed April 2018 to July 2022 were included. The Wnt signaling pathway was activated in 922 (47.8%) patients. Wnt pathway activation varied substantially across GI cancers, from 81.1% in colorectal cancer (CRC) to 3.4% in anal cancer. APC was the most commonly altered gene in CRC, small bowel and biliary carcinomas. CTNNB1 was predominant in liver (41.2%), MEN1 in neuroendocrine (14.6%), and RNF43 in gastric (9.4%) cancer. Of 921 patients with alterations in the Wnt pathway, 5.2% had a co-mutation in another Wnt pathway-related gene. RSPO2/3 fusions were found in 4 CRC, 1 stomach, 1 biliary, and 1 small bowel cancer and were mutually exclusive with other alterations in the Wnt pathway. Conclusions: Wnt signaling is activated in about half of all GI cancers, and APC alterations are the most frequently observed. Whole transcriptome profiling allowed us to identify RSPO2/3 fusions, which also contribute to activation of the Wnt pathway. Wnt activation appears to be a particularly important in CRC, with 81.1% of CRC having a Wnt pathway alteration. Our results highlight the therapeutic potential of targeting the abnormal Wnt/β-catenin signaling pathway in GI malignancies. [Table: see text]
A phase II study of hypofractionated radiation therapy to augment immune response in patients with metastatic gastrointestinal malignancies progressing on immune therapy (ARM-GI).
Authors: Hewitt Chang, Luchia Andemicael, Moshiur Mekhail Anwar, John Gordan, Jamese Johnson, Bridget P Keenan, Robin Kate Kelley, Andrew H. Ko, Katherine Van Loon, Alan P. Venook, Lawrence Fong, Melody Ju Xu, Mary Uan-Sian Feng
Journal: Journal of Clinical Oncology (2023)

TPS817 Background: Metastatic disease remains a consistent challenge for patients with gastrointestinal (GI) malignancies. Multiple immune checkpoint inhibitors (ICI) have been FDA approved for several GI indications. Still, patients will progress on these therapies, either immediately or after initial response. Palliative radiation therapy (RT) is an effective treatment that can be delivered to symptomatic metastases. It also has been reported to lead to an abscopal effect, which is an induction of response in a distant tumor. This is thought to result from increased tumor immunogenicity, tumor microenvironment modulation, and immune cell recruitment. Thus, palliative RT could not only relieve symptoms, but also potentially reinvigorate the immune response, prolong ICI efficacy, and delay next-line systemic therapy that carries risks of unknown efficacy and tolerability. Ongoing studies seek to elucidate prognostic and predictive biomarkers of the abscopal effect. However, cohorts of patients with GI malignancies are limited, so there remains a need for research in combining RT and immunotherapy in the context of metastatic GI cancer. ARM-GI aims to study the radiation-augmented immune response in patients with metastatic GI cancers progressing on immunotherapy. Methods: ARM-GI is a phase 2, single arm study. Key eligibility criteria include confirmed metastatic GI malignancy, progressive disease per RECIST v1.1 on any ICI, and at least 2 metastases, one of which can be safely left unirradiated. The target prescription dose is 30 Gy in 5 fractions to symptomatic sites through intensity modulated RT or stereotactic body RT. Patients will continue the same immunotherapy after RT and be evaluated per RECIST v1.1 longitudinally. The primary endpoint is overall response rate (ORR) per RECIST v1.1. Secondary endpoints include ORR per iRECIST, progression free survival, overall survival, local control in radiated lesion(s), effect of distant radiation on unirradiated target lesions, incidence of new metastatic lesions, safety by CTCAE v5.0, and time to new systemic therapy. The study will enroll 28 patients, with recruitment ongoing. Serial peripheral blood samples are collected for exploratory studies that will analyze for association with disease response and quantification of changes in circulating immune cell subsets after RT compared to baseline. Clinical trial information: NCT04221893 .
Survival of patients with colorectal cancer (CRC) with low expression of homologous recombination proficient (HRP) genes.
Authors: Daniel Walden, Sachin Deshmukh, Felipe Batalini, Binbin Zheng-Lin, Sharon Wu, Joanne Xiu, Emil Lou, Daniel H. Ahn, Christina Wu, Sanjay Goel, Anthony Frank Shields, David Spetzler, Matthew James Oberley, Wolfgang Michael Korn, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2023)

225 Background: HR deficient (HRD) CRC has improved outcomes following exposure to DNA damaging agent (DDA) (irinotecan, IR; oxaliplatin, OX) compared to HRP CRC. Low expression of wild type (WT) BRCA1 mRNA is associated with prolonged OS in ovarian cancer; however, this finding has not been investigated in CRC or outside of BRCA. Here, we examine the effect of low expression of HR genes in HRP CRC on post-DDA survival. Methods: 12,860 CRC samples were analyzed by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq) at Caris Life Sciences (Phoenix, AZ). Samples were classified by RNA expression percentiles. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first of OX or IR to last contact. Results: Post-IR survival was prolonged with low expression of ATM, CHEK2 and PALB2 in WT ATM, PALB2, and CHEK2 WT CRC, respectively (bottom vs. top 10%, bottom vs. top 25%; p&lt;0.05). Notably, low PALB2 expression (bottom 10%) showed a 14.5-month post-IR benefit compared to high PALB2 expression (top 10%) in WT PALB2 CRC (p=0.003). Post-OX survival was not significantly prolonged with low expression of CHEK2 in WT CHEK2 CRC (bottom 10% vs top 10%, bottom 25% vs top 25%) but was with low expression of ATM (+9.7 months, p=0.02) and PALB2 (+5.6 months, p=0.03) in WT ATM and PALB2 CRC, respectively (all bottom 25% vs top 25%). Conclusions: Here we report the first findings to suggest a novel subclass of CRC defined as the low expression of mRNA of non-mutated HRD genes that exhibit sensitivity to DDA. Low expression of WT ATM, CHEK2, and PALB2 correlates with prolonged OS following IR, post-OX survival was prolonged with low expression of ATM and PALB2. Further characterization defining sensitivity of low expressing HRP genes to DDA may help guide treatment considerations in HRP CRC. [Table: see text]
Treatment sequencing for patients with localized duodenal and ampullary adenocarcinoma.
Authors: Abhishek Janardan, Ben George, Gulrayz Ahmed, Sherin Daniel, Bicky Thapa, Maahum Mehdi, Lisa Rein, Aniko Szabo, Beth Erickson, William A. Hall, Kathleen K. Christians, Susan Tsai, Douglas B. Evans, Mandana Kamgar
Journal: Journal of Clinical Oncology (2023)

783 Background: Duodenal adenocarcinomas (DA) and ampullary adenocarcinoma (AA) are rare, comprising less than 1% of all gastrointestinal cancers. Optimal treatment sequencing strategies for patients with localized DA and AA have not been prospectively validated. We analyzed the clinical outcomes of patients with localized DA and AA treated with curative intent, multimodality therapy based on treatment sequencing – upfront surgery versus neoadjuvant therapy. Methods: Our institutional database was interrogated to identify adult patients with localized DA and AA diagnosed between January 2000 to December 2019. Adjusted survival analyses were performed to compare outcomes of patients that received neoadjuvant therapy (NAT - concurrent chemo-radiation +/-induction chemotherapy) versus upfront surgery (+/- adjuvant chemotherapy). Survival time was calculated from date of diagnosis to either death (overall survival; OS) or relapse/death (relapse free survival; RFS). Log-rank test and multiple Cox proportional hazards regression were performed to compare survival between treatment groups and adjust for relevant variables. Results: We identified 79 patients – 32 (41%) with DA and 47 (59%) with AA; Median age at diagnosis was 67. Forty two patients (53%) were male. Sixty-two patients underwent surgery – 27 (43.6%) patients with DA and 35 patients (56.4%) with AA. Among patients with DA, 18 (67%) were treated with upfront surgery, while 9 (33%) were treated with NAT. Among patients with AA, 32 (91%) were treated with upfront surgery while 3 (9%) were treated with NAT. Lymph node (LN) positivity rate in DA and AA patients treated with upfront surgery was 15% and 46% respectively, compared to 50% and 0% respectively, in patients treated with NAT (p = 0.26, p &gt; 0.99 respectively). DA patients treated with upfront surgery had a median relapse free survival (mRFS) of 3.8 years compared to 1.4 years for those treated with NAT (p = 0.370). The median overall survival m(OS) was not reached (NR) for DA patients treated with upfront surgery (4 years +) or NAT (2.6 years +) p = 0.875). AA patients treated with upfront surgery had a median RFS of 4.7 years compared to NR for patients treated with NAT (p = 0.117) while the mOS of AA patients treated with upfront surgery and NAT were 5.9 years and NR respectively (p = 0.158). Conclusions: Among DA patients, there was no difference in outcome based on sequence of treatment delivery – NAT versus upfront surgery. DA patients with more aggressive clinical phenotype were likely treated with NAT, hence similar outcomes in both groups should prompt consideration of NAT for all patients with DA. Role of NAT in AA is not clear considering the small sample size.
Efficacy of adjuvant fluoropyrimidine with or without oxaliplatin therapy in older adults with mismatch repair deficient stage III colorectal cancer.
Authors: Jerod J Sears, Zishuo Ian Hu, Jingxia Liu, Samuel Ballentine
Journal: Journal of Clinical Oncology (2023)

112 Background: Standard adjuvant chemotherapy regimens for Stage III colorectal cancer (CRC) include FOLFOX/CAPOX, 5-FU/capecitabine, or observation alone. There is uncertainty around the therapeutic benefit of adding oxaliplatin to fluorouracil in older adults over the age of 70 with Stage III CRC, including in those with mismatch repair–deficient (MMR-D) CRC. In this single institutional study, we evaluate progression free survival (PFS) across a 12-year period in patients who receive FOLFOX/CAPOX or 5-FU/capecitabine compared to active surveillance in older adults with MMR-D Stage III CRC. Methods: We identified patients diagnosed with MMR-D Stage III CRC after the age of 70 who received care at our institution and affiliates between 2005-2019. We performed a retrospective chart review of patient outcomes during the 12-year follow up period based on chemotherapy regimen to determine PFS. Patients without MMR-D staining performed at initial time of diagnosis had MMR protein immunohistochemistry performed currently and included in the analysis. Results: Among patients with MMR-D stage III CRC, 50%, 62.5%, and 76% of patients were alive at the end of year 12 with no disease progression in the observation, 5-FU/capecitabine, and FOLFOX/CAPOX groups. The PFS probabilities at one year are 69.6%, 87.5%, and 87.0%, and at five years are 41.8%, 62.5%, and 87.0% in these groups, respectively. Finally, there was a statistically significant difference (P=0.039) in PFS across all chemotherapy regimens in the MMR-D cohort. Conclusions: Based on this study, older adult patients with stage III MMR-D colorectal cancer have an improved progression free survival when treated with oxaliplatin containing chemotherapy compared to active surveillance alone. [Table: see text]
The efficacy of capecitabine as a salvage treatment in metastatic colorectal cancer after prior 5-fluorouracil–included chemotherapies.
Authors: Jae Yeon Jang, hyun-Jin Bang, Woo Kyun Bae, Seung-Shin Lee, Soonil Lee, Kwang Yong Shim, Jee Hyun Kong, Yundeok Kim, Seungtaek Lim
Journal: Journal of Clinical Oncology (2023)

54 Background: We aimed to retrospectively analyze the efficacy and toxicity of capecitabine, as a salvage treatment, in metastatic colorectal cancer (mCRC) that progressed after prior standard 5FU included chemotherapies. Methods: From January 1, 2008, to December 31, 2017, patients with mCRC, age ≥ 18, who received capecitabine as third- or fourth-line treatment at five different centers in South Korea, were included. All had disease progression on prior palliative chemotherapies including 5FU, oxaliplatin, and/or irinotecan. Results: A total of 131 patients were analyzed with a median age of 62 (range, 35-87). Almost all patients were exposed to prior 5FU (100%), irinotecan (100%), and oxaliplatin (98.5%). Patients were treated with cetuximab (26.7%), or bevacizumab (45.8%) before capecitabine. The median and mean duration from the last 5FU exposure to capecitabine start were 21 and 67.3 days, respectively (range, 5-1322). The objective response rate (ORR) of capecitabine was 3.6%, and the disease control rate was 30.4%. The median progression free survival (mPFS) and median overall survival (mOS) was 2.77 (95% CI, 2.495-3.045) and 9.60 months (95% CI, 7.625-11.575), respectively. There was a significant difference in efficacy according to the duration from the last 5FU exposure to the time of starting capecitabine. Compared to patients who started capecitabine earlier than 67 days after the last 5-FU administration, those who started capecitabine later than that time showed higher ORR (11.1% vs 1.2%; p-value = 0.043), mPFS (4.430 (95% CI, 2.274-6.586) vs 2.570 months (95% CI, 2.326-2.814); p-value = 0.011), and mOS (14.070 (95% CI, 5.627-22.513) vs 9.500 months (95% CI, 7.370-11.630, p-value = 0.021) (Table). 68.7% patients experienced any grade of adverse events, but only 4.6% complained grade 3 or higher. There was no treatment related death. Conclusions: Capecitabine showed modest antitumor activity with good tolerability in mCRC patients whose disease progressed after oxaliplatin and/or irinotecan. It could be considered as an alternative treatment option for mCRC patients, especially for those who have longer treatment free interval after 5FU based chemotherapies. [Table: see text]
Real world data of systemic therapy for hepatocellular carcinoma in Japan: HERITAGE study.
Authors: Yoshinari Asaoka, Ryosuke Tateishi, Yasuhide Yamada, Hiroko Iijima, Naoya Kato, Mitsuo Shimada, Etsuro Hatano, Takumi Fukumoto, Takamichi Murakami, Hirohisa Yano, Kengo Yoshimitsu, Masayuki Kurosaki, Michiie Sakamoto, Yutaka Matsuyama, Masatoshi Kudo, Norihiro Kokudo
Journal: Journal of Clinical Oncology (2023)

510 Background: Currently 6 regimens are available for advanced hepatocellular carcinoma (HCC) in Japan, including atezolizumab plus bevacizumab (AB), sorafenib (S), and lenvatinib (L) for first-line treatment and regorafenib (R), ramucirumab (RAM), and cabozantinib (C) for the second-line treatment. In real-world clinical practice, the number of combinations of treatment sequences is enormous. We have launched a nationwide registry of systemic therapy for HCC named Hepatoma Registry of Integrating and Aggregating Electric Health Records (HERITAGE). Methods: The HERITAGE is linked to the nationwide follow-up survey of the Japan Liver Cancer Association; cases treated with systemic therapy between 2015 and 2022 were included in the current study. Information on treatment efficacy and duration was collected and registered on each treatment regimen. Results: As of June 2022, 6,400 treatment lines (S 2,319, L 2559, AB 768, R 406, RAM 251, C 71) in 4,307 cases were enrolled. The response rates, disease control rates, and median treatment duration of each sequence of regimens are shown in the table. The 1 st line regimen, S, L, and AB, were also used as the second and later lines in Japan and found as effective as if used as the 1 st line treatment. Limitation: No adjustments for clinical conditions were performed. Conclusions: We have demonstrated the efficacy of various treatment sequences in a sufficient number of cases. Clinical trial information: UMIN000046567 . [Table: see text]
Interim analysis results of gut microbiota in patients with unresectable cholangiopancreatic cancer: SCRUM-Japan MONSTAR-SCREEN.
Authors: Shun Tezuka, Shunsuke Sakai, Riu Yamashita, Satoshi Horasawa, Takao Fujisawa, Kentaro Sawada, Ayumu Yoshikawa, Yoshiaki Nakamura, Kumiko Umemoto, Nobuhiro Shibata, Koushiro Ohtsubo, Shinji Itoh, Akiko Todaka, Kentaro Sudo, Masayuki Furukawa, Masafumi Ikeda, Chigusa Morizane, Makoto Ueno, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2023)

733 Background: MONSTAR-SCREEN prospectively assessed the gut microbiota of 2000 patients (pts) with advanced solid cancer at 31 Japanese institutions. Here, we report the interim analysis results of the correlation between gut microbiota and the efficacy of first-line chemotherapy in pts with unresectable pancreatic cancer (PC) and bile tract cancer (BTC). Methods: We analyzed unresectable 205 PC and 83 BTC pts with clinical data as data cut-off on April 30, 2021, and 16S ribosome analysis results of stool samples. Among PC pts, 133 and 40 were treated with GnP (gemcitabine (GEM) plus nab-paclitaxel) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), respectively. Among BTC pts, 32 and 33 were treated with GC (GEM plus cisplatin) and GCS (GEM, cisplatin, plus S-1), respectively. Pts with an above-median overall survival (OS) were defined as long-term survivors (LTS), and those with below-median OS and OS events were defined as short-term survivors (STS). We compared the alpha diversity index (ADI) of LTS and STS, and identified potential microbial biomarkers of LTS, STS, responders, and non-responders to first-line chemotherapy according to RECIST version 1.1, by linear discriminant analysis effect size (LEfSe). In each cohort, the top three microbiota with linear discriminant analysis scores of ≥ 3.0 were considered significant. Results: The median OS of PC and BTC pts was 13.5 and 15.9 months, respectively. In PC pts, no significant difference was noted in the ADI between LTS (n=20) and STS (n=40). In BTC pts, the ADI of LTS (n=10) was significantly higher than that of STS (n=20) in the Shannon index. LEfSe analysis in PC pts revealed that Burkholderiales and Sutterellaceae were predominant in LTS, while Lactobacillaceae was, in STS. In PC pts, Brachyspiraceae and Erysipelotrichales were predominant in responders (n=67), while Enterococcaceae and Lactobacillaceae were, in non-responders (n=137). In BTC pts, Peptostreptococcaceae, Fusobacteriaceae, and Clostridiaceae in LTS; Cardiobacteriaceae, Prevotellaceae, and Actinobacteriota in responders (n=24); and Bacilli in non-responders (n=59) were overrepresented. Conclusions: This interim analysis identified potential biomarkers of the gut microbiota that may contribute to the prognosis and efficacy of chemotherapy in pts with unresectable PC and BTC. The results of this analysis will be validated in the primary analysis.
Multiagent neoadjuvant chemotherapy compared to upfront surgery in pancreatic cancer of the body and tail using the National Cancer Database.
Authors: Oskar Franklin, Toshitaka Sugawara, Salvador Rodriguez Franco, Richard D. Schulick, Marco Del Chiaro
Journal: Journal of Clinical Oncology (2023)

722 Background: While neoadjuvant chemotherapy is increasingly being using in pancreatic cancer treatment, it is unclear whether it is beneficial in treatment of body and tail tumors. Randomized controlled trials are lacking and previous observational studies have not demonstrated any benefit. We aimed to assess survival associations, trends over time and patient selection associations for multiagent neoadjuvant chemotherapy treated pancreatic cancer of the body and tail using data from the National Cancer Database (NCDB). Methods: We queried the NCDB for pancreatic adenocarcinoma in the body or tail diagnosed between 2010 – 2018 that received multiagent neoadjuvant chemotherapy and/or a distal pancreatectomy. Patients with clinical M1, clinical T4 and surgery other than partial pancreatectomy were excluded. Survival was compared with Kaplan-Meier estimates and multivariable Cox Proportional Hazard Estimates. Results: Between 2010 – 2018, the use of multiagent neoadjuvant chemotherapy increased from 5.7% to 31.8%. In total, 1951 patients were included with n = 384 receiving multiagent neoadjuvant chemotherapy (cases) and n = 1567 undergoing upfront surgery (controls). Neoadjuvant chemotherapy was associated with younger age, tumor in the pancreatic body, clinical N1-2 and with Ca 19-9 ≥98 U/mL. Neoadjuvant chemotherapy was associated with a decreased mortality rate in multivariable Cox regression models adjusting for preoperatively assessed variables (HR 0.65, 95% CI 0.53 – 0.81, p &lt; 0.001) and results were significant in both clinical T1-2 and T3 tumors. Patients treated with upfront surgery had higher rates of adjuvant chemotherapy receipt after resection (41.4% vs 70.6%) but there was no difference in R1 resection rates or 90-day postoperative mortality between the groups. The addition of neoadjuvant radiotherapy was not associated with improved survival in patients receiving neoadjuvant chemotherapy. Conclusions: Multiagent neoadjuvant chemotherapy is increasingly being used in the treatment of pancreatic cancer of the body and tail, especially in younger patients and patients with more aggressive tumor characteristics. Multiagent neoadjuvant chemotherapy is associated with improved survival but randomized trials are needed to establish causal relationships.